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Abstract

New neurons continue to be generated in the subgranular zone of the dentate gyrus of the adult mammalian hippocampus1,2,3,4,5. This process has been linked to learning and memory, stress and exercise, and is thought to be altered in neurological disease6,7,8,9,10. In humans, some studies have suggested that hundreds of new neurons are added to the adult dentate gyrus every day11, whereas other studies find many fewer putative new neurons12,13,14. Despite these discrepancies, it is generally believed that the adult human hippocampus continues to generate new neurons. Here we show that a defined population of progenitor cells does not coalesce in the subgranular zone during human fetal or postnatal development. We also find that the number of proliferating progenitors and young neurons in the dentate gyrus declines sharply during the first year of life and only a few isolated young neurons are observed by 7 and 13 years of age. In adult patients with epilepsy and healthy adults (18–77 years; n = 17 post-mortem samples from controls; n = 12 surgical resection samples from patients with epilepsy), young neurons were not detected in the dentate gyrus. In the monkey (Macaca mulatta) hippocampus, proliferation of neurons in the subgranular zone was found in early postnatal life, but this diminished during juvenile development as neurogenesis decreased. We conclude that recruitment of young neurons to the primate hippocampus decreases rapidly during the first years of life, and that neurogenesis in the dentate gyrus does not continue, or is extremely rare, in adult humans. The early decline in hippocampal neurogenesis raises questions about how the function of the dentate gyrus differs between humans and other species in which adult hippocampal neurogenesis is preserved.

Acknowledgements

We thank the families who donated the tissue samples used in this study, and J. Rodriguez, V. Tang, J. Cotter and C. Guinto for technical support. S.F.S. was supported by F32 MH103003 and M.F.P. was supported by K08 NS091537. A.A.-B. was supported by NIH grants P01 NS083513, R01 NS028478 and a gift from the John G. Bowes Research Fund. He is the Heather and Melanie Muss Endowed Chair and Professor of Neurological Surgery at UCSF and is a co-founder and serves on the scientific advisory board of Neurona Therapeutics. G.W.M. was partly supported by the Davies/Crandall Endowed Chair For Epilepsy Research at UCLA. G.W.M. and J.C. were supported by NIH NINDS (NS083823 and U01 MH108898). M.C.O. was supported by a Scholar Award from the UCSF Weill Institute for Neurosciences. We acknowledge NSFC grants to Z.Y. (31425011, 31630032, and 31421091). S.M. was supported by fellowships from the European Molecular Biology Organization (EMBO Long-Term Fellowship, ALTF_393-2015) and the German Research Foundation (DFG, MA 7374/1-1). J.M.G.-V. and A.C.-S. were supported by MINECO/FEDER Grant BFU2015-64207-P, Red de Terapia Celular TerCel, Instituto de Salud Carlos III (ISCIII2012-RED-19-016 and RD12/0019/0028) and PROMETEOII/2014/075.

Author information

Affiliations

Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, California 94143, USA

Shawn F. Sorrells

, Mercedes F. Paredes

, Kadellyn Sandoval

, Kevin W. Kelley

, David James

, Simone Mayer

, Arnold R. Kriegstein

, Michael C. Oldham

& Arturo Alvarez-Buylla

Department of Neurological Surgery, University of California San Francisco, San Francisco, California 94143, USA

Shawn F. Sorrells

, Kurtis I. Auguste

, Edward F. Chang

, Michael C. Oldham

& Arturo Alvarez-Buylla

Department of Neurology, University of California San Francisco, San Francisco, California 94143, USA

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Contributions

M.F.P. and S.F.S. contributed equally as co-first authors and A.C.-S., K.S. and D.Q. contributed equally as second authors. Z.Y., A.A.-B., M.F.P. and S.F.S. conceived the study. A.A.-B., S.F.S. and M.F.P. designed and interpreted the experiments and, with A.C.-S., K.S., D.Q., S.M. and D.J., conducted the experiments. K.I.A., E.F.C., J.C., E.J.H., A.J.G., A.R.K. and G.W.M. assisted with specimen collection and conducted clinical and neuropathological reviews. K.W.K. and M.C.O. designed and performed the bioinformatic analyses. A.C.-S. and J.M.G.-V. conducted and interpreted the ultrastructural studies. S.F.S., M.F.P., A.C.-S. and K.S. prepared the figures. A.A.-B., S.F.S. and M.F.P. wrote the manuscript with input from all authors.

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Editorial Summary

No new neurons in adult humans

Previous lines of evidence have suggested that neural precursors are present in adult humans and continue to generate new neurons in the hippocampus even after full maturation. Here, Arturo Alvarez-Buylla and colleagues re-visit that concept and come to a different conclusion. Using a more comprehensive and larger set of samples of human hippocampus than those analysed in previous studies, the authors find evidence for the production of new neurons early in life, but note that hippocampal neurogenesis rates decline rapidly within the first few years of childhood. The authors were unable to detect the production of any new neurons in adults. The same patterns of neurogenesis were observed in rhesus macaques.